The compound 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thi ophene, known also by its generic chemical name, raloxifene, is an important member of the class of compounds known as selective estrogen receptor modulators(SERMs). That compound is disclosed in U.S. Pat. No. 4,418,068.
Some of the compounds prepared by the present processes, including raloxifene, were first described in U.S. Pat. No. 4,133,814. That patent taught the use of phenacyl, halophenacyl, and alkyl protecting groups for phenolic hydroxyl groups. Those alkyl protecting groups may be removed by treating the phenolic ethers with pyridine hydrochloride.
The process described in U.S. Pat. No. 4,358,593 used additional protecting groups (for example, acetyl, substituted acetyl, benzoyl, alkylsulfonyl, and arylsulfonyl groups) for preparing 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl]-benzo[b]thiophe nes. That patent further taught the use of classical Friedel-Crafts catalysts in the acylation of the protected 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene, including metal halides such as aluminum chloride, aluminum bromide, zinc chloride, boron trifluoride, boron tribromide, titanium tetrachloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride, and ferric chloride. Subsequent to acylation, the protecting group was generally removed under basic conditions.
The process described in U.S. Pat. No. 5,470,854 taught the use of methyl protecting groups that could be cleaved in a one pot process during the Friedel-Crafts acylation by particular acylation catalysts. That patent taught that boron halides, such as boron trichloride and boron tribromide, were particularly useful in the Friedel-Crafts acylation, and for the cleavage of arylmethyl ethers.